By Lisa Spear

Key takeaways:

• ​​Cognitive impairment—including problems with attention, memory, and executive function—can persist in people with narcolepsy even when sleepiness is treated, suggesting a separate pathophysiology.
• Surveys show that up to three-quarters of patients on approved narcolepsy therapies still experience cognitive symptoms, which patients rank among their most burdensome.
• Research is exploring orexin-2 receptor agonists such as Takeda’s oveporexton (TAK-861), which in phase 3 trials improved objective and subjective cognitive measures.
• EEG-based tools like Beacon Biosignals’ Waveband headband and behavioral tasks such as the psychomotor vigilance test are being studied to quantify and monitor cognitive dysfunction in narcolepsy.
• Clinicians often overlook “brain fog” because patients describe it in nonmedical language, highlighting the need for standardized definitions and dedicated assessment tools.

A man in his 40s sat in front of clinical psychologist Christopher Wendel, PhD, DBSM, one early afternoon on the grey couch where Wendel sees all his behavioral sleep therapy clients. “What brings you in?” Wendel asked.

Silence hung in the air. The man slumped forward, his eyes downward. He twirled his wrist out in front of him, as if to try to pluck the words out of the air, but the words didn’t come. Finally, he looked up and said, “Narcolepsy.” The man booked this appointment months ago and had driven 30 minutes to get here—yet summoning the right language to describe why he found himself sitting on a couch at The Ohio State University Wexner Medical Center seemed like a challenge.

Word-finding issues, like the kind that the man experienced, are some of the more common indicators of cognitive impairment that people with narcolepsy present with, Wendel says. Cognitive challenges are generally assumed to be a consequence of sleepiness, but even when people with narcolepsy are at their most alert, like the man who came to Wendel’s office, for instance, cognitive impairment can still be notable. Sleep specialists are now theorizing that cognitive impairments in narcolepsy—including issues with sustained attention, memory, and planning—are not just a side effect of sleepiness, but distinct symptoms with their own pathophysiology.

“Sometimes sleepiness improves with treatment, but problems with brain fog and thinking clearly linger,” says Kiran Maski, MD, MPH, a neurologist-sleep physician at Boston Children’s Hospital and an associate professor of neurology at Harvard Medical School. “Perhaps treating daytime sleepiness isn’t sufficient for treating brain fog.”

In fact, emerging evidence shows that the current standard of care does not adequately address cognitive problems. A recent survey of 203 adults with narcolepsy type I found that 74% still experienced cognitive impairments despite being on a US Food and Drug Administration-approved narcolepsy pharmacotherapy ¹

Another survey of 1,699 people with narcolepsy (types 1 and 2) reports that cognitive impairments are some of the most burdensome symptoms. Half of all respondents reported cognitive difficulties, which came in second only to excessive daytime sleepiness, as the most significant symptom impacting their daily lives.² Still, cognitive impairments remain underrecognized in narcolepsy, according to a recent paper authored by researchers at Harvard Medical School and Takeda.³

Stakeholders are now showing interest in investigating why people with narcolepsy experience cognitive issues, the potential origins of these challenges, and ways to evaluate and target these impairments. There are hopes that finding the mechanisms behind cognitive impairment could lead to more recognition, and perhaps more precise treatments down the line.

Currently in the pipeline, pharmaceutical company Takeda has a narcolepsy drug candidate that shows promise in improving cognitive impairment. It recently completed two double-blind, placebo-controlled phase 3 trials examining the effects of the orexin-2 receptor agonist oveporexton (TAK-861).

According to information provided by Takeda, the oveporexton improved both objective neuropsychological test results and subjective patient-reported outcomes. Patients saw notable improvements in attention, memory, and executive function.

“We are really seeing incredible benefits that haven’t been seen to date in terms of treating cognitive symptoms” in narcolepsy, says Brian Harel, PhD, senior scientific director at Takeda. “We are seeing dramatic improvements across the board. In fact, many patients are returning to normal limits on these tests.” Takeda plans to present the full dataset on cognition from the phase 3 oveporexton studies at SLEEP 2026.

The cognitive improvements could be directly related to modulating orexin neurotransmission. Severe loss of orexin-producing neurons could be the biological cause of cognitive symptoms, but research is still needed to confirm this theory. The cause of narcolepsy type 2 remains unknown, but it may be due to less extensive loss of orexin-producing neurons, so some of these same mechanisms may also apply.⁴

“We are getting more information about the location of orexin receptors,” Maski says. Orexin receptors are in the cortex, the part of the brain responsible for higher-level functions like thinking, language, and sensory processing. Orexin receptors are even present in the hippocampus, the area of the brain important for converting short-term memories into long-term memories. When orexin is low, it could have a direct impact on those neuronal areas, potentially impacting cognition.

Additionally, researchers are looking at ways to use electroencephalogram (EEG) technology to measure cognitive impairments in hypersomnia disorders.

Sleep scientists from the company Beacon Biosignals presented data at SLEEP 2025 and World Sleep-Singapore 2025 outlining how the Waveband EEG headband (formerly Dreem 3S) could be used to monitor patients.⁵

“The idea is to utilize daytime brain function biomarkers to not only look for sleep states but look for microsleeps and arousals to correlate with cognition and also look at other spectral features and waveforms that we know are related to cognition,” says Matthew Alkaitis, MD, PhD, chief clinical officer at Beacon Biosignals and clinical assistant professor at Stanford School of Medicine.

The EEG device can pick up microsleeps during the day, which might explain some of the cognitive impairment seen in narcolepsy.

The research, in partnership with Takeda, captures quantitative sleep data in narcolepsy type 1 patients. The research was able to validate sleep staging in this patient population compared to in-lab polysomnography and show that patients could wear the device for 24-hour periods to capture and quantify daytime naps and micro-naps.

“We think this technology could be an incredibly useful tool to identify quantitative neurophysiological biomarkers that track with daytime sleepiness and cognitive symptoms,” Alkaitis says.

Additionally, Harvard Medical School researchers are investigating behavioral tools to measure the cognitive impairments seen in narcolepsy. They are studying the utility of the psychomotor vigilance task, one of the cognitive assessments to measure sustained attention and reaction time. The test involves having a patient respond to a visual stimulus that appears at random intervals.

While the psychomotor vigilance task is used primarily in research, there is potential for its deployment to evaluate narcolepsy in clinical settings. If the tool shows value by not just assessing baseline severity but also can assess outcomes after treatment, that might justify its use in clinical settings as well.

“The psychomotor vigilance task is a well-known task that shows us significant differences between control populations and adults and children with narcolepsy. This task could potentially be a useful assessment tool for assessing attention and alertness, a dimension of brain fog,” Maski says.

While awareness is spreading about the significance of brain fog in narcolepsy, there is still work to do in developing standardized ways to measure cognitive impairments and develop formal definitions around how to talk about cognitive issues in narcolepsy.

Patients often forgo specifically mentioning cognitive issues, so it falls to the clinicians to recognize signs of impairment. In many cases, people with narcolepsy might not realize there is a connection with sustained attention, memory, and planning problems.

In narcolepsy advocate Julie Flygare’s case, before getting a diagnosis, she lived a busy life as a law school student, downplaying the symptoms that she experienced. All she could think about when the teacher stood in front of the class to talk about property law was: “Try to keep your eyes open. Try to keep your eyes open.” By the end of the class, her notes were a “jumbled mess.”

In these moments, she thought the sleepiness was the main problem. Flygare didn’t realize she had experienced cognitive symptoms until after a few months on oxybate and a stimulant. Then, one night when she found herself studying in the law library, it hit her all at once: “The connections in my brain were moving and I could remember what I read.” An effortlessness in her cognitive functioning that she hadn’t experienced in years came over her, says Flygare, who is now the president and CEO of Project Sleep.

“When your brain works, you don’t really think about it. It is effortless. No weight on your skull. It doesn’t feel like anything.”

Even when patients do recognize their symptoms, they might use more colloquial language like “brain fog” to describe their experience. The term brain fog has no consistent formal medical definition, and it falls on medical professionals to ask the right questions to decode what their patients are experiencing.

“It’s pretty common in my experience for patients to…note the symptoms almost in passing, rather than using medical terms or clinical language,” says Wendel. “I suspect the cognitive symptoms are underrecognized partially because it’s easy to underestimate the frequency and severity of symptoms that are presented in this way unless providers are actively listening for cognitive symptoms.”

Sleep specialists typically focus on excessive daytime sleepiness, so they might use a tool like the Epworth Sleepiness Scale to assess whether a therapy is efficacious and then stop there. Establishing a solid medical definition of brain fog would be helpful, so it gets the clinical recognition that it needs. This way, appropriate tests could be established and implemented both objectively and subjectively, Maski says.

In the future, Maski hopes that research will help decode the pathophysiology of brain fog, in narcolepsy and in other conditions. In the meantime, there are behavioral modifications that can help people with narcolepsy manage their cognitive symptoms. Providers can guide their patients to life hacks that might improve their functioning in work or school, including using alerts on phones to keep track of important tasks or meetings. Writing down important tasks in assignment notebooks can help to stay organized. Project Sleep, a non-profit dedicated to raising awareness about sleep health, has also produced a Narcolepsy and Brain Fog toolkit to help patients navigate cognitive symptoms.

Even just letting people with narcolepsy know that their cognitive impairments are common for people with their condition can make a world of difference in making them feel less alone. Many patients with narcolepsy have never met someone else with the condition. The man who sat in Wendel’s therapy office didn’t realize there was a connection between his challenges finding words and his narcolepsy.

“I reassured him that these kinds of challenges are something that a lot of folks with narcolepsy experience,” Wendel says. ““It was really a relief for him to hear.” The man immediately perked up. Nobody had ever talked to him about cognitive impairment as a symptom of narcolepsy before. 

References

1. Thorpy M, Kant A, Harper K, et al. Crescendo: Results from a survey of symptom burden and quality of life in patients with narcolepsy type 1. Neurology. 2025 Apr 8;7(supp_1):2879.

2. Maski K, Steinhart E, Williams D, et al. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden, and treatment efficacy. J Clin Sleep Med. 2017;13(3):419-25.

3. Cano CA, Harel BT, Scammell TE. Impaired cognition in narcolepsy: clinical and neurobiological perspectives. Sleep. 2024 Sep 9;47(9):zsae150

4. Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009;32(8):993-8.

5. Reh R, Karas M, Chan AM, et al. Evaluation of Dreem 3S for sleep monitoring and diagnosis in narcolepsy type 1. 2025 June. SLEEP 2025 poster P532.

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